Extended Data Fig. 10: Working model.

CCM3 acts as a gatekeeper in focal adhesion sites, regulating FAK/Src-induced mechanotransduction and YAP/TAZ signalling. The FAT domain of CCM3 mutually competes with the FAT domain of FAK for the binding to paxillin. The consequence of this competition is the attenuation of FAK/Src activation, actomyosin coupling, traction forces on the ECM, and focal adhesion signalling. When CCM3 is lost from focal adhesions, its inhibitory function no longer attenuates FAK/Src-induced mechanotransduction and YAP/TAZ activation. The recruitment of CCM3 to focal adhesions has biological importance. Loss of CCM3 in CAFs drives the recruitment and activation of CAFs, reorganises the collagen and ECM network, and consequently leads to changes in tumour stiffness and increased metastatic dissemination. Perturbation of CCM3 in MSCs influences the efficacy of stem cell differentiation. High level of CCM3 in focal adhesions supports adipogenesis, while low levels of CCM3 is beneficial during osteogenesis. Created with BioRender.com.